To improve my chemistry, i revisit some synthetic route seen in literature, only on paper with a small bibliographic study to check the feasibility of some hypothesis, with chemical and process optimization for industrialization.
In the search field below, type a reactions class (ex: alkylation) or name (ex: Lossen rearrangement) to find the message containing the link to the report which use the desired reaction. Also, references are clickable in reports.

-The
process described in the patent for the compound 6 (an in house product) use a
toxic reagent to prepare the 2-[(aminocarbonyl)amino] : chlorosulfonylisocyanate.

Alternate route proposal:

Cheaper starting materials (1336 $/kg less)
but with 2 more steps (thiophene moiety excluded since this is an in-house product). This route avoids a cryogenic stage with n-Hexyl lithium
(health and safety and plant capabilities considerations), and optionally
avoids the use of boronic derivatives which are now classified as mutagenic.

Sum-up of the modifications:

Modification of the
starting material with three possibilities, essentially to introduce the
isoxazole moiety: According to some lectures about the VNS of H (reference mentioned
later), it maybe possible to use 1-halo-2-nitrobenzene which is cheaper (27$/kg
(Cl) 101$/kg (F) – molbase) and 3-chloropentane-2,4-dione (358$/kg), to take
advantage of the nitro EWG behavior. It will be reduced later, followed by a diazotation
and CuBr/KBr or KI dependently of the method, which will avoid a cryogenic
step. Also, to go back to the original route, the diazonium salt could be
reacted with B2(OH­)4 which afford the boronic derivative
(see reference later)

If doesn’t work, 1-chloro-5-fluoro-2-nitrobenzene
probably do, which is unfortunately more expensive than the trihalobenzene (675$/kg
– molbase), but the exceeding price of 480$/kg should be absorbed by other
starting materials, pentane-2,4-dione (110$/kg - molbase) and hydroxylamine sulfate
(25$/kg - molbase).

6 is an in-house
product, but to avoid the use of the toxic reagent, i will use in this
proposal, the 2-amino-3-cyano-thiophene (450 $/kg – mol base), which is
commercially available and treat it with CDI/formamide to obtain the
2-[(aminocarbonyl)amino].

Also if the original
compound 6 is used, an exchange could be made with i-PrMgClBis[2-(N,N-dimethylamino)ethyl]
Ether Complexes, followed by a treatment with trimethylborate which lead to the
boronic acid derivatives (see reference), instead of using the unstable aryl
boronic derivative.

This is
some personal works on paper only, i have no responsibility in any way if
somebody would try this route and has all sort of troubles, including but not
limited to: injuries and money loss. This is for experienced chemists only, and
tests must be conducted in a suitable lab only.

But if my work is used
to synthesize the targeted molecule described here, please, send a word, even
if it fails, chemistry is always an experimental science. This will make me
pleased, thank you.